Andexanet Alfa Fully Neutralizes Anticoagulation From Thrombotic Disorder Treatment

Andexanet alfa (AA), a molecularly modified recombinant coagulation factor Xa (FXa), is able to fully neutralize the anticoagulant effects of factor Xa inhibitors used for thrombotic disorders, suggest study findings published in Clinical and Applied Thrombosis/Hemostasis, which showed a concentration-dependent effect of the antidote.

Similar to other anticoagulants, FXa inhibitors approved in this setting—apixaban, edoxaban, and rivaroxaban—come with risks of uncontrolled and life-threatening bleeding. In 2018, the FDA granted accelerated approval to AA as an antidote for the reversal of apixaban and rivaroxaban anticoagulation. More recent data show that AA may also have the same effect for edoxaban and betrixaban, the latter approved but currently off the market.

Taking a whole thromboelastographic approach to their analysis, the researchers found that the anticoagulant effects of the anti-Xa agents were partially neutralized at an AA dose of 50 mcg/mL and were completely neutralized at 100 mcg/mL. The 2 concentrations were based on recommended dosing regimens. The researchers argue, based on their findings, that thromboelastography is a reliable approach to comparing the anticoagulant effects of these agents and their neutralization.

The group chose a fixed concentration of 1 mcg/mL for the FXa inhibitors, at which dose they all produced some anticoagulant effect, finding that edoxaban had the largest anticoagulant effect, followed by betrixaban, rivaroxaban, and apixaban.

“Apixaban had the weakest anticoagulant effect but was also the least neutralized by AA at both concentrations,” wrote the researchers, noting that looking at both R-time and K-time, AA at both concentrations showed slower neutralization for apixaban than the other agents. They added, “Regarding R-time and K-time, the apixaban-AA system lags in comparison to betrixaban and rivaroxaban. This leads to further questions as to why AA at both concentrations neutralizes apixaban the least when it has the smallest anticoagulant effect of the agents.”

At 50 mcg/mL, AA had the most anticoagulant effect on rivaroxaban, followed by betrixaban, edoxaban, and apixaban. In the R-time parameter, the rivaroxaban-AA system had less than a 2-minute difference from saline—used as a control in the study—suggesting that the lower concentration of AA can fully neutralize the anticoagulant effects of the FXa inhibitor. The K-time parameter showed that the betrixaban-AA system was most neutralized while apixaban was least neutralized. Similar findings were seen in the angle parameter, and in the max amplitude parameter, edoxaban had the weakest clot formation.

Less variability was observed with the higher dose, which yielded complete neutralization across the board. Notably, at 100 mcg/mL of AA, R-time measurements for betrixaban and edoxaban showed faster coagulation than saline, revealing a possibility of “overneutralization” if too much AA is administered. The angle parameter showed that clot formation was similar between the agents, although edoxaban and rivaroxaban showed slightly faster saline control.

The researchers noted that the dosing regimen of each of the 4 agents varied greatly and may reach different concentrations to produce therapeutic and supratherapeutic effects. The pharmacokinetics also follow different patterns.

Reference

Mehrotra S, Hoppendteadt D, Jeske W, et al. Differential Neutralization of Apixaban, Betrixaban, Edoxaban, and Rivaroxaban by Andexanet Alfa as Measured by Whole Blood Thromboelastographic Analysis. Clin Appl Thromb Hemost. 2022;28:10760296221138297. doi:10.1177/10760296221138297